Thiocyanohydrine derivatives of the steroid series and process of making same



United Patent THIOCYANOHYDRINE DERIVATIVES OF THE gTEROID SERIES ANDPROCESS OF MAKIN i No Drawing. Filed Apr. 15, 1958, Ser. No. 728,523

2 Claims. c1. 260-39745 This invention relates to novel thiocyanohydrinederivatives of compounds of the steroid series. More partic ularly, theinvention concerns a novel method for the preparation of thiocyanoderivatives of t-hecholestane, androstane, and pregnene series.

Thiocyanohydrines of the steroid series havenot heretofore' beendescribed in the literature. Some thiocyanosteroids have already beenprepared, utilizing therefor as starting materials either halogenatedsteroids and exchanging the halogen for the thiocyano. group byconversion with alkali thiocyanates, or else, by treating 3-ketosteroids with dithiocyano compounds under ultraviolet light. Both ofthese methods do not lead to thiocyanohydrines.

It has now been found, in accordance with this invention, thatthiocyanohydrines of the steroid series may be obtained in a simple,reaction starting with steroid epoxides and treating the epoxides withthiocyanic acid. Preferably, an excess of the thiocyanic acid is used;thereby the epoxide bonds aresevered, with addition of the thiocyanicacid. Salts of thiocyanic acid with organic bases may also be employed,for example salts of tertiary bases, such as pyridine.

As starting materials for the novel process of this invention, there maybe used epoxides of the steoroid series,

in which the steroid'molecule may be either saturated or I unsaturated,and furthermore may contain other additional substituents such as oxygenand/or hydroxy groups, and may contain a side chain at the l7-carbon.Advantageously, there may be used 9,6,115- and Sa,6aepoxides, which aresplit ed with an excess of thiocyanic P C6 v 2 bly sensitive steroid isalways kept apart from the nonsteroids by means of the acid, since thereaction only takes place at the phase boundaries.

In accordance with this invention, a considerable excess ofconcentrated, aqueous thiocyanic acid is preferably used. Inasmuch ashighly concentrated aqueous thiocyanic acid is very unstable(decomposing, inter alia, into hydrogen sulfide, hydrogen cyanide,-andforming polythiocyano compounds), the epoxide splitting occurs only withcomparatively strong concentrations of thiocyanic acid. The formation ofpolythiocyano compounds is prevented by working under nitrogen. 'Anypolythiocyano compounds formed may beqreadily removed.

It was further found, in accordance with the invention;

that the splitting of the epoxides of steroids takes place underparticularly favorable conditions when the epoxides are heated with thethiocyanate salts of organic bases, especially tertiary bases such aspyridine, in a solvent under reflux. In such case, the pyridiniumthiocyanate is preferably used in excess, for example, 5 mols. There maybe used as solvents, for example, ethanol, or acetone, or similarsolvents. There may also be used, as a solvent, however, a tertiary basesuch as the one used for salt formation. j 7

The splitting of simple aliphatic or cyclic alkylene oxides withethereal thiocyanic acid is known. 'In such case the alkylene oxides areusedin excess and after com;-

pletion of the reaction the excess oxide is distilled off. It 7 couldnot be predicted from this circumstance, however, that a process of thisgeneral type would be adaptable to such complexly constituted andvariably reactable'compounds as the steroids. -As a matter of fact, theprocess of the present invention diifers from the previously knownmethod in that an excess of thiocyanic acid is used. A

' removal of the epoxides by. distillation,paralleling the knownalkylene oxide method, would be out of the questionin the case ofsteroidcompounds. These pseudohalogen compounds, particularly where thethiocyano group occupies the 6- or 9-position, canbe used as such astherapeutic agents, or they can serve as acid. Thereby there are formedpredominantly 9ozand 6B-thiocyanosteroids. The process can also becarried out so that the thiocyanic acid isallowed to act upon theepoxide in an inert organic solvent, in which the epoxide is likewisesoluble, such as, for example,'ether. 'This method is especiallydesirable for readily dissociable epoxides, such as, for example, the5a,6u-epoxides., It

is more advantageous, however, to operate in a two phase system. In sucha system, concentrated, aqueous thiocyanic acid (about25%) acts upon thesteroid ep'oxide,

which is dissolved in an inert solvent which is immiscible.

with water, such as, advantageously, a halogenated hydrocarbon, I forexample, methylene chloride or "chloro form. Upon shaking for severalhours at room temperature, preferably with exclusion of light and in anatmosphere of nitrogen, the introduction of the thiocyano group takesplace. I p p a The foregoing method possesses the following advantagesover the use ofethereal thiocyanicacid;,,

(a) Improved solubility of most steroid epoxides halogenatedhydrocarbons as compared withether;

' (b) Higher concentration of, aqueonsithiocyanic acid.

is possible than in ether; I t

(c) In contrast to the single ph ase method, possiintermediates forconversion into pharmaceuticall y valu ably steroid compounds. Thus, forexample, 9a'-thio cyano-llB-hydroxy-l7o -methyl-testosterone is avaluable anabolic agent. 9a-thiocyano-hydrocortisone 21 ace tate is anactive cortical hormonehaving an. anti-inflam matory action of the typecharacteristic of hydrocortisone as evidenced by the glycogen testandthe thymus ,test.

The new thiocyanohydrines of the steroid series are'also valuableas'intermediates' since by known methods the thiocyano group may betransformed into -SH, -SS-, S-alkyl,--SO H, or OH groups, and

by splitting off water they can be transformed into mi- 7 saturatedthiocyanohydrines. An example of a product resulting from splittingofl'water' is- 6-thiocyano-17uhydroxy-progesterone acetate, whichexhibits-anfactivity similar ,to that of 17orhydroxyprogesteroneacetate.' It

is noteworthy that the above-mentioned transformations.

of the thiocyano group take place evensmore readily in the case of theproducts of splitting otf'water than in'the case of'the'thiocyanohydnnes themselves. The preparation of these novelthiocyanohydrines for:

the first timeopens up new paths to thepi'eparatiomof useful steroidcompounds, which heretofore were obtai able innoknownmanneri" Y iThexfollowing examples serve :to illustrate-'vario embodiments of'thenovel proce ss'of this invention, p

EXAMPLE 1 I l HO SON 1.00 g. of a,6-oxidocho1estane-3;3'ol are dissolvedin 4.0. ml. of methylene chloride and treated with 13.5 ml. of an ethersolution of thiocyanic acid (molar ratio of epoxide to acid is 1:5). Themixture is allowed to stand in the dark at room temperature for 4-8hours. The. organic liquid phase is washed until neutral and free ofthiocyanate with sodium bicarbonate solution and finally with water, anddried over Na SO After concentrating and rubbing the residue withacetone, there were crystallized 0.65 g. of613-thiocyanocho1estane-3,9,5u-diol, which after two recrystallizationsfrom ethyl acetate melted at l83-l84. (A product recrystallized fromacetone contains acetone of crystallization and melts at 176-177.)

1 Analysis: C H O NS.-Ca1culated: C, 72.8%; H, 10.26%; N, 3.07%; S,6.9%. Found: C, 73.1%; H, 10.3%; N, 3.05%; S, 6.5%.

/ a/ -5 1.8. (methylene chloride: c=0.01)

IR: hgfiif =2.90/2.96/3.52/4.63/6.80/6.86/7.28/7.28/8.08/

EXAMPLE 2 6B-thiocyano-ch0lestane-3fi,5a-diol phase is washed with Wateruntil free from thiocyanate or pyridine and dried over sodium sulfate.Yield is 5.35 g. after a single recrystallization from acetone; M. Pt.173-174.

7 EXAMPLE 3 p A dB-thiocyano-choIestane-3;3,5c-diol 2.00 'g. of5a,6-oxidocliolestane-313-01 are dissolved in 100 ml. of methylenechloride or chloroform and 4, f. 7 EXAMPLE 4 9a-thx'0cyano-I 1fl-hydroxy-I 7m-methyltestosterone 7 ate; the precipitated polythiocyanocompounds are reusual way until thiocyanate-free, and dried'over. sodiumshaken for 18- hoursin the dark under nitrogen'with I 90 ml. of anapproximately 25% aqueous thiocyanic acid solution at room temperature;Finally excess thiocyanic acid is neutralized to a Weakly acid reactionwith solid sodium bicarbonate; then the mixture is freed fromprecipitatcdx polythiocyano compounds bysuction filtration.After-separationof the organic phase, the residue is twice extgacteiwithmethylene,- chloride, and the combined extracts are washed withsodium,bicarbonatesolution and Water, u-ntil thiocyanate-free. andneutral; and dried over sodiumg'sulfate. The; yield after rubbing withacetone is 1.76, g. M.: Pt.-1'74-176, After recrystallization from Yethyl acetate the inelting point rises to l83-184. v

sulfate. The crude product. is recrystallized from ethyl acetate; yield1.35 g., M. Pt. 133-140'.

Upon recrystallization from ethyl acetate and from acetonehexane therewere obtained 0.68 g. of Ju-thiocyano-11p-hydroxy-l7ix-methyltestosterone having a M. Pt. 148-149 (decomp).

Analysis: C H O NS'.Calculated: C, 67.17%; H, 7.79%; N, 3.73%; S, 8.53%.Found: C, 67.6%; H, 7.9%; N, 3.9%; S, 8.4%.

' /oz/ +196. (Acetone: 0:0.01.)

IR: X31:2.92/3.05(Schulter)/3.43/4.68/5.99/6.18/8.08/9.37/10.56/-1l.58/13.15/-13.20; UV: e =14910 \EXAMPLE 5 r9a-thiocyano-hydrocortisone-ZI -aceza te' crno'ac dione-Zl-acetate aredissolved. in 275 ml. of methylene chloride or chloroform are shakenwith 220 ml. of an approximately 25% aqueous thiocyanic acid solution atroom. temperature for 18 hours in the dark under nitrogen.Proces'singtakes place as in Example'4. The crude product yields, whenrubbed with methanol, 3.66 g. of crystalline9a'-thiocyano-hydrocortisoneil-acetate, or thiocyano Apregnene-11B,l7ot,21-triol-3',20-dione-2lacetate; after doublerecrystallization from acetone-hexaii.

drines. The described steroid rhodanhydrines tend toward the addition ofsolvent of crystallization; acetone of crystallization and ethyl acetateof crystallization were observed.

EXAMPLE 6 1 g. of 5u,6-oxidopregnane-3 8-ol-20-one are dissolved in 50m1. of methylene chloride or chloroform and shaken in the dark undernitrogen at room temperature for 17 hours with 40 m1. of an aqueous 25%solution of thiocyanic acid. The processing corresponds to that in /oc/+14 (Methylenechloride: c=0.01) IR )\,=2.962.99 (OH)/4.67 (SCN)/5.88p(20-CO) EXAMPLE 7 1 6 B-th iocyano-A pregnene-3 5,1 7 a-diol-20-orie-3J7- diacetate m: For:

, one.

10 g. of 16a,l7-oxidoA -pregnene-313-01-20-one-3-acctate are dissolvedin 215 ml. of glacial acetic acid and treated with a glacial aceticacid-thiocyanic acid solution (a mixture of 10.7 g. of 100% sulfuricacid, 130 mol. glacial acetic acid, and g. of dry sodium thiocyanate) atroom temperature with vigorous stirring during about minutes; theoperation is carried out under a current of nitrogen.

Finally the mixture is heated 1% hours with stirring at IOU-105 bathtemperature. The mixture is cooled in an ice bath and stirred into anexcess of ice water (about 2.5 liters). The precipitated compound isfiltered ofi by suction, washed thoroughly with ice water, dissolved inmethylene chloride, filtered and dried over sodium sulfate. 'Uponconcentration in vacuo there results 11.8 g. of crude compound.

The crude product (3-monoacetate), is first purified by doublerecrystallization from methanol, or by simple partition betweendimethylsulfoxide/ether-hexane; the l7u-OH group of the prepurifiedproduct is acetylated with acetic anhydride in presence ofp-toluenesulfonic acid. After the usual processing and doublerecrystallization from methanol there are obtained 3.3 g. of the3,17-diacetate, M. Pt. 235.5237.

Analysis: C H O NS.-Calculated: C, 65.9%; H, 7.45%; N, 2.96%; S, 6.77%.Found: C, 66.0%; H, 7.9%; N, 3.2%; S, 6.7%.

/a/ |l8 (Methylenechloride; c=0.01)

IR A; =4.67 (-SCN)/5.78u (3 and 17-aeetate; C=O)/ 5.86 (Schulter)20CO/8.03p, 8.18 (Schulter) Acetate/ 9.67;; (Acetate) /Weaker OH-Bandsat 2.95;],

We claim: 1. 9oz thiocyano 1118 hydroxy-17u-methyltestoster- 2.9a-thiocyanohydrocortisone-2l-acetate.

No references cited.

1. 9A-THIOCYANO-11B-HYDROXY-17 A-METHYLTESTOSTERONE.